Vasopeptidases are enzymes responsible for the generation or inactivation of vasoactive peptides. As such, vasopeptidase inhibition represents a significant approach for the treatment of cardiovascular disease. For example, angiotensin-converting enzyme (ACE) inhibitors are FDA approved and widely used to treat hypertension and heart failure. In addition, inhibitors of two other vasopeptidases, neprilysin (NEP) and endothelin-converting enzyme (ECE), are currently in preclinical and clinical development as are combined inhibitors of these enzymes. Recently, considerable data has emerged indicating a role for the vasopeptidases ECE and NEP, and perhaps also ACE, in the degradation of the Alzheimer's amyloid beta-peptide (ABeta). As the abnormal accumulation of ABeta plays a pivotal role in AD pathogenesis, pharmacological inhibition of these vasopeptidases is of considerable concern as they may increase ABeta levels in a manner that increases risk of developing Alzheimer's disease. In this application we propose to directly evaluate the hypothesis that chronic reductions in ECE, NEP, and ACE will result in enhanced ABeta accumulation and AD-like pathology by examining the effects of mice genetically deficient in these enzymes and mice treated with clinically relevant vasopeptidase inhibitors. The results of these studies will further our understanding of the role of NEP, ECE, and ACE in determining ABeta concentration in the brain, while helping to assess the potential risk of the clinical use of vasopeptidase inhibitors.